1. Field of the Invention (Technical Field)
The present invention relates to lactam-bridged melanocortin receptor-specific cyclic peptides which may be used in the treatment of melanocortin receptor-mediated diseases, indications, conditions and syndromes.
2. Description of Related Art
The following discussion refers to a number of publications by author(s) and year of publication, and that due to recent publication dates certain publications are not to be considered as prior art vis-a-vis the present invention. Discussion of such publications herein is given for more complete background and is not to be construed as an admission that such publications are prior art for patentability determination purposes.
A family of melanocortin receptor types and subtypes have been identified, including melanocortin-1 receptors (MC1-R) expressed on normal human melanocytes and melanoma cells, melanocortin-2 receptors (MC2-R) for ACTH (adrenocorticotropin) expressed in cells of the adrenal gland, melanocortin-3 and melanocortin-4 receptors (MC3-R and MC4-R) expressed primarily in cells in the hypothalamus, mid-brain and brainstem, and melanocortin-5 receptors (MC5-R), expressed in a wide distribution of peripheral tissues. MC1-R has been suggested to be associated with hair and skin pigmentation and inflammation, MC2-R is believed to mediate steroidogenesis, MC3-R has been suggested to be associated with energy homeostasis, food intake, and inflammation, MC4-R is believed to control feeding behavior, energy homeostasis, and sexual function (e.g. erectile function), and MC5-R has been suggested to be involved in the exocrine gland system.
Significant work has been done in determining the structure of melanocortin receptors, including both the nucleic acid sequences encoding for the receptors and the amino acid sequences constituting the receptors. MC4-R is a G protein-coupled, 7-transmembrane receptor that is believed to be expressed primarily in the brain.
MC4-R inactivation has been shown to result in obesity (Hadley, 1999, Ann N Y Acad Sci, 885:1-21). Agouti-related protein (AgRP) is an endogeneous compound that has been suggested to be a MC antagonist or an inverse agonist on MC4-R. The α-melanocyte stimulating hormone (α-MSH) is believed to be the principle endogenous MC4-R agonist.
Also peripherally located MC4-R receptors have been suggested to be involved in the control of energy homeostasis, and the role of MC4-R signalling in the vagus nerve and its relevance for treatment of obesity and diabetes is discussed by Gautron et al, The Journal of Comparative Neurology, 518:6-24 (2010).
Peptides specific for MC4-R, and secondarily peptides specific for MC3-R, are believed to be useful in regulation of mammalian energy homeostasis, including use as agents for attenuating food intake and body weight gain. MC4-R agonist peptides are believed to be useful for treating sexual dysfunction, including male erectile dysfunction, and for decreasing food intake and body weight gain, such as for treatment of obesity. Such peptides may also be employed for decreasing voluntary ethanol consumption, treatment of drug addictions, and the like. MC4-R agonist peptides, as well as MC3-R agonist peptides, may further be employed for treatment of circulatory shock, ischemia, hemorrhagic shock, inflammatory diseases and related diseases, indications, conditions and syndromes. MC4-R antagonist peptides, by contrast, are believed to be useful for weight gain aid, such as for use in treatment of cachexia, sarcopenia, wasting syndrome or disease, and anorexia. Such peptides may also be employed for treatment of depression and related disorders. (Wikberg et al, Nature Reviews, Drug Discovery, 7, 307, (2008); Adan et al, British J. Pharm., 149, 815-827 (2006); Nogueiras et al, J. Clin., Invest., 117(11): 3475-3488 (2007); Maaser et al, Ann. N.Y. Acad. Sci., 1072, 123-134 (2006); Giuliani et al, British J. Pharm., 150, 595-603 (2007); Balbani, Expert Opin. Ther. Patents, 17(3), 287-297 (2007); and Navarro et al, Alcohol. Clin. Exp. Res., 29(6), 949-957 (2005)).
Melanocortin receptor-specific cyclic peptides include cyclic α-melanocyte-stimulating hormone (“α-MSH”) analog peptides such as Ac-Nle-cyclo(-Asp-His-D-Phe-Arg-Trp-Lys)-NH2 (See U.S. Pat. Nos. 5,674,839 and 5,576,290) and Ac-Nle-cyclo(-Asp-His-D-Phe-Arg-Trp-Lys)-OH (See U.S. Pat. Nos. 6,579,968 and 6,794,489). These and other melanocortin receptor-specific peptides generally contain the central tetrapeptide sequence of native α-MSH, His6-Phe7-Arg8-Trp9 (SEQ ID NO:1), or a mimetic or variation thereof, such as the substitution of D-Phe for Phe'. Other peptides or peptide-like compounds asserted to be specific for one or more melanocortin receptors are disclosed in U.S. Pat. Nos. 5,731,408, 6,054,556, 6,350,430, 6,476,187, 6,600,015, 6,613,874, 6,693,165, 6,699,873, 6,887,846, 6,951,916, 7,008,925, 7,176,279 and 7,517,854; in U.S. published patent application Publication Nos. 2001/0056179, 2002/0143141, 2003/0064921, 2003/0105024, 2003/0212002, 2004/0023859, 2005/0130901, 2005/0187164, 2005/0239711, 2006/0105951, 2006/0111281, 2006/0293223, 2007/0027091, 2007/0105759, 2007/0123453, 2007/0244054, 2008/0004213, 2008/0039387, and 2008/0305152; and in international patent applications nos. WO 98/27113, WO 99/21571, WO 00/05263, WO 99/54358, WO 00/35952, WO 00/58361, WO 01/30808, WO 01/52880, WO 01/74844, WO 01/85930, WO 01/90140, WO 02/18437, WO 02/26774, WO 03/006604, WO 2004/046166, WO 2004/099246, WO 2005/000338, WO 2005/000339, WO 2005/000877, WO 2005/030797, WO 2005/060985, WO 2006/012667, WO 2006/048449, WO 2006/048450, WO 2006/048451, WO 2006/048452, WO 2006/097526, WO 2007/008684, WO 2007/008704, WO 2007/009894, WO 2008/025094, and WO 2009/061411. Melanocortin receptor-specific cyclic peptides disclosed in the foregoing are typically cyclized through a lactam bridge formed by the side chains of Asp (aspartic acid) and Lys (lysine), or alternatively through a disulfide bridge formed by the side chains of two Cys (cysteine) or other reactive thiol-containing residues.
Melanocortin receptor-specific linear peptides are known which contain Glu (glutamic acid) and Orn (ornithine), including certain linear peptides disclosed in WO2008/025094 and U.S. Pat. No. 5,674,839. Cyclic peptides asserted to be specific for one or more melanocortin receptors and containing a Glu and Orn are known, but are peptides in which the cyclic portion thereof consists of seven amino acids, such as those disclosed in U.S. Pat. Nos. 6,951,916 and 6,613,874. In such peptides, there are five amino acids between the Glu and Orn residues, and thus the cyclic peptide ring contains 26 ring atoms.
Melanocortin receptor-specific peptides may be evaluated by a number of parameters, including binding affinities (typically Ki values reported in nM) and various functional measures, such as EC50 and Emax values. While melanocortin receptor-specific cyclic peptides are reported with nanomolar or subnanomolar Ki values, for pharmaceutical development for many indications it is desired and necessary to optimize functionality, such as EC50 and Emax values, such that the peptides are agonists, preferably full agonists, more preferably potent full agonists, with nanomolar or subnanomolar EC50 values and Emax values as high as feasible, such as over about 80%, about 90% or at or over 100%. It is against this background that the present invention was made.